Over the years, extensive progress has been made in the characterization of tau and its role in the fibrillar pathology of Alzheimer's disease and other tauopathies. Many biochemical models for the self assembly of tau have been used to further ascertain some of the fundamental properties of tau filament assembly. For example, multiple groups have identified which domains on the tau molecule are required for filament polymerization. At present, however, little is known about how tau filaments that characterize a number of neurodegenerative diseases form within neurons and glia. A primary goal of this proposal will be to design a human cell culture system for tau filament accumulation, and to characterize the impact of tau filament accumulation on cell function. The primary hindrance to tau filament assembly -- de novo nucleation of filaments -- will be bypassed by microinjecting pre-assembled tau filaments into cell lines stably expressing transfected tau. These experiments will provide insight into the stability of intracellular tau filaments and determine if tau filaments are relatively inert, as has been proposed in the lamprey model of tau filament accumulation, or whether tau filaments can have a significant impact upon basic cellular function.